Rosuvastatin and Losartan Pharmacokinetics After Bariatric Surgery

N/ANot Yet RecruitingNCT07748273

Hospital das Clínicas de Ribeirão Preto60 enrolled

Overview

This prospective, open-label, non-randomized pharmacokinetic study will evaluate how Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy affect systemic exposure to single oral test doses of rosuvastatin and losartan. Sixty adults scheduled for bariatric surgery will enter one of two parallel groups according to the clinically selected operation (30 RYGB and 30 sleeve gastrectomy). Each participant will receive rosuvastatin 10 mg and losartan 25 mg once within 30 days before surgery and again approximately 12 weeks after surgery. Plasma samples collected before dosing and at 1.5 and 4 hours after dosing will be used with maximum a posteriori Bayesian estimation to estimate individual pharmacokinetic parameters. In the 30-participant RYGB group only, paired stool samples will be used to explore gut microbiota and untargeted fecal metabolomic changes. The primary objective is to compare within-participant changes and between-procedure differences in drug exposure after bariatric surgery.

Anatomical and physiological changes after bariatric surgery may alter oral drug absorption, first-pass metabolism, transporter activity, and systemic exposure. RYGB bypasses the duodenum and proximal jejunum, whereas sleeve gastrectomy preserves intestinal continuity but reduces gastric volume and may accelerate gastric emptying. Rosuvastatin is strongly influenced by transporters such as OATP1B1 and BCRP; losartan is affected by absorption and CYP2C9-mediated formation of its active metabolite E-3174. Direct comparative evidence between these procedures is limited. Eligible adults will be enrolled before clinically indicated surgery. Surgical procedure selection is not assigned by the study. At each pharmacokinetic visit, after at least 8 hours of fasting, participants will receive single oral doses of rosuvastatin 10 mg and losartan 25 mg with 200 mL water. Venous plasma samples will be obtained at 0, 1.5, and 4 hours. Concentrations of rosuvastatin, losartan, and E-3174 will be quantified using validated HPLC-MS/MS. Individual AUC0-infinity, apparent clearance, half-life, and apparent volume of distribution will be estimated using MAP Bayesian methods informed by published population pharmacokinetic models. Clinical and laboratory covariates, including weight, BMI, lipid profile, blood pressure, comorbidities, and concomitant medications, will be recorded. In the 30-participant RYGB group only, paired stool samples will be analyzed by 16S rRNA sequencing and untargeted metabolomics. Safety will be monitored during and after each research dosing visit.

Study Type

INTERVENTIONAL

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Adults aged 18 to 65 years; * Formal clinical indication for RYGB or sleeve gastrectomy after multidisciplinary assessment; * Bariatric surgery scheduled and no previous bariatric procedure; * Able to understand the study and provide written informed consent. Exclusion Criteria: * Moderate or severe hepatic impairment, liver enzymes greater than 3 times the upper limit of normal, or Child-Pugh class B or C. * Estimated glomerular filtration rate below 30 mL/min/1.73 m². * Concomitant use of drugs that substantially affect rosuvastatin pharmacokinetics and cannot be temporarily discontinued, including cyclosporine, gemfibrozil, or potent OATP1B1/BCRP or CYP2C9 inhibitors. * Systemic antibiotic use within 3 months or probiotic, prebiotic, or synbiotic use within 4 weeks before sampling. * Continuous current rosuvastatin or other statin therapy unless medically discontinued with an adequate washout period under physician supervision. * Clinically relevant baseline hypotension, significant hyperkalemia, renal impairment, or another condition that makes a losartan test dose unsafe. * Severe postoperative complication preventing oral dosing, including active gastrointestinal leak, intractable vomiting, or severe anastomotic stenosis. * Pregnancy. Participants of childbearing potential undergo routine preoperative beta-hCG testing.

Outcomes

Primary Outcomes

Change in rosuvastatin area under the plasma concentration-time curve extrapolated to infinity (AUC0-infinity)

Individual rosuvastatin AUC0-infinity will be estimated from plasma concentrations at 0, 1.5, and 4 hours using maximum a posteriori Bayesian estimation based on a published population pharmacokinetic model. Within-participant postoperative/preoperative geometric mean ratios and between-procedure differences will be estimated.

Time frame: Within 30 days before surgery and approximately 12 weeks after surgery (postoperative visit may be delayed up to 6 months for clinical safety).

Change in losartan area under the plasma concentration-time curve extrapolated to infinity (AUC0-infinity)

Individual losartan AUC0-infinity will be estimated using the same sparse-sampling MAP Bayesian strategy and a published parent-metabolite population model.